ALS MEETING CONTINUES
WITH NITTY-GRITTY OF
CLINICAL TRIALS AS FOCUS

by Margaret Wahl

TARRYTOWN, N.Y., June 15, 2003 – The second part of MDA’s ALS Clinical Trials: The Challenge of the Next Century conference was devoted to understanding and improving the conduct of ALS trials. Sessions included presentations on markers of disease progression; determination of outcome measure (end points) in trials; statistical methodology; the merits of various trial designs, including placebo group design and other approaches to using untreated comparison groups; large and small research collaborations; and calls to action.

DEFINING THE ‘NATURAL HISTORY’ OF ALS

Nigel Leigh of King’s College Hospital in London posed the question of whether the natural progression of ALS is changing.

Determining this is important, because many trials of new drugs or other therapies seek to compare the treated group with the untreated disease -- its natural history.

When Leigh’s group compared ALS patients from before 1996 to those after 1996, he found there was a 14 percent increase in the probability of surviving for five years.

Leigh attributed the increase in five-year survival to better general care in ALS, including more widespread use of noninvasive ventilation and more attention to nutrition with insertion of feeding tubes when needed, as well as to widespread use of the drug riluzole.

He cautioned against relying on older natural history data as a baseline for comparison of data from a treated group in a trial, since the experimental treatment might in fact not be better than today’s standard care.

Ben Brooks, who directs the MDA/ALS Center at the University of Wisconsin-Madison, says his studies suggest that riluzole may have more of an effect on ALS early in the progress of the disease than it does later and that much of the survival improvement since 1996 can be attributed to riluzole use.

He also noted that there may be factors in ALS that determine the way patients respond to treatments, including riluzole and any experimental compounds being considered, and that it’s important to consider these factors if they can be identified.

For instance, he said, age, site of onset of symptoms (whether in the bulbar muscles, which control the mouth and throat, or in the limb muscles), and the stage at which a treatment is started could have a large impact on the trial results.

Edward Kasarskis of the University of Kentucky in Lexington noted that use of feeding (gastrostomy) tubes and positive-pressure ventilation are “uncontrolled variables” in ALS trials. He said that investigators have assumed that these factors would “wash out” because they would by chance be approximately equally used by those receiving the treatment and those in the untreated (control) groups, but that he was not entirely convinced of the truth of this assumption.

For instance, he noted, if an experimental drug were to increase or decrease weight or appetite, it might influence a patient’s decision about using a feeding tube and thus blur the effects of the experimental medication alone.

FINDING TRIAL ‘END POINTS’

Jesse Cedarbaum of Regeneron Pharmaceuticals explored the question of which outcomes to look for in clinical trials.

These outcomes, known as “end points,” have traditionally been length of survival in the treated and untreated groups, muscle strength differences in the compared groups, pulmonary function differences, or quality-of-life differences.

Cedarbaum suggested that other measures might be more indicative of a treatment’s success or failure. For one thing, he said, it’s becoming more difficult to define “survival” in ALS now that ventilation can prolong life to an indefinite extent.

The difference in physical status between a person who chooses to use ventilation and one who doesn’t may be minimal, or there may be none at all, but the person who chooses ventilation will likely survive longer, thus obscuring the measurable effect of any tested treatment.

Cedarbaum said that the timing of disease progression, the rate of functional decline, or quality-of-life measures may be good alternatives to survival as outcome measures, or end points, in an ALS trial.

SCALES AND MEASURES -- WHICH ONE IS BEST?

Another group of lectures concerned the selection of measurements that lead to clinical end points.

The speakers included Richard Smith of the Center for Neurologic Study in La Jolla, Calif.; Stanley Appel, who directs the MDA/ALS Center at Baylor College of Medicine in Houston; Paul Gordon, who is a co-director of the MDA/ALS Center at Columbia Presbyterian Medical Center in New York; Merit Cudkowicz, who is associated with the MDA/ALS Center at Massachusetts General Hospital in Boston; Eric Sorenson of the Mayo Clinic in Rochester, Minn.; and Bruce Barton of the Maryland Medical Research Institute in Baltimore.

They discussed the pros and cons of several systems of measuring the effects of ALS: a scale that asks patients to report on the number of incidents of uncontrolled laughing or crying that occurred in a given week (the CNS Lability Scale); the Appel ALS Scale, which assigns point values to tests of muscle strength in the speech and swallowing muscles, respiratory muscles, arm muscles and leg muscles; the revised version of the ALS Functional Rating Scale, which measures activities of daily living and overall function, including respiratory symptoms; tests that measure maximum voluntary muscle contraction in the arms, legs and respiratory muscles; and manual muscle testing, in which an examiner estimates the subject’s muscle strength by asking him or her to resist the examiner’s own muscular efforts and scoring the results in a standardized manner.

Barton, a statistician, discussed the need to choose a scale or measurement system that can best estimate the most likely therapeutic effect of the experimental treatment. If, for instance, the drug is expected to affect strength, the investigators should use the measures that are most sensitive to changes in strength.

The chosen measure should be minimally sensitive to factors that could confuse the results, and examiners or patients ought to be able to complete the measurements or scales with as few errors and as little missing information as possible, he noted.

BIOLOGICAL MARKERS OF DISEASE PROGRESSION

Research in certain other diseases, such as cancer and AIDS, is guided by reliable biological markers of disease progression -- identifiable signs that the disease is worsening, improving or staying about the same. Cancer trials, for example, have long been guided by tumor size and extent of spread (staging) and by blood levels of various molecules, such as prostate-specific antigen, or cell counts.

In ALS, such biological indicators have been scarce but some exist, the experts noted, and can be used to answer certain types of questions that arise in clinical research. Finding new and better markers, they suggested, should be a priority in current ALS investigations.

The lecturers in this section included M. Flint Beal of Weill Medical College of Cornell University in New York; Clifton Gooch of Columbia University in New York; Jeremy Shefner, director of the MDA/ALS Center at Upstate Medical University in Syracuse, N.Y.; Michael Swash of Royal London Hospital in England; and Douglas Arnold of McGill University in Montreal.

A “motor unit” is a muscle-controlling nerve cell in the spinal cord with the fibers that connect it to muscle cells. Counting these motor units, a technique called MUNE, for “motor unit number estimation,” can be used to measure their loss during the course of ALS. The technique requires electrophysiological studies and the ability to interpret the complex signals that emerge from these.

If done correctly, MUNE can provide an accurate biological marker of at least some aspects of disease progression.

Another marker that relies on electrophysiology measurements is the “neurophysiological index,” which is the result of a mathematical calculation that combines the strength and timing of electrical signals from muscles and nerves.

Magnetic resonance spectroscopy (MRS), which is noninvasive and relatively comfortable for patients, can determine the status of nerve cells in the brain by measuring the density of two chemicals, NAA and creatine, and their relationship to each other.

Among the future targets, according to Beal at Cornell, are 20 recently identified compounds in the blood plasma that investigators believe may be correlated with ALS progression.

DESIGNING STUDIES

Testing a new drug or other therapy may sound easy, but designing a trial that can reliably tell the difference between disease progression in people who got the treatment and those who didn’t and provide assurance that results reflect only that difference is extremely challenging.

Robert Miller, director of the MDA/ALS Center at California Pacific Medical Center in San Francisco; Yuko Palesch of the Medical University of South Carolina; Dan Moore of the University of California at San Francisco; and Stanley Appel, director of the MDA/ALS Center at Baylor College of Medicine in Houston, each gave lectures that stimulated much discussion of trial design strategies.

Innovative designs included some in which each participant receives a placebo (inert substance) and then the study drug (without knowing when the switch occurs), and in which the investigators compare progress during the placebo phase and treatment phase during later analysis. Every participant has a chance to take the study drug in this design, and comparisons are made between the placebo and the treatment phase for each person, not between groups of people.

One design, presented by Yuko Palesch, has been designed to screen out ineffective treatments quickly and avoid unnecessary exposure to these substances or wasting of time and resources.

Informally known as a “futility study,” this design compares those taking the drug to statistics on untreated patients derived from databases. The investigators conduct a short trial to see whether the drug warrants further investigation.

If the drug is not eliminated at this stage, Palesch cautioned, it’s essential that patients and doctors not interpret this to mean that the drug is in fact effective. Futility trials are designed only to eliminate poorly performing drugs and not to measure positive effects, he said.

Stanley Appel discussed the use of “historical controls” instead of placebo controls as untreated comparison groups in trials. Historical controls are extracted from databases that have recorded the progress of untreated patients.

He said that the disease progression scores taken from a database of untreated patients at Baylor look the same as those of patients who received a placebo in several drug trials, leading him to conclude that historical controls are a valid tool as a placebo group substitute.

Appel’s group used the Appel ALS Scale to take disease progression measurements for the database.

He noted that survival increased from an average of 30 months in the 1980s to an average of about 40 months between 1997 and 2001. He said the earlier data could be problematic if used as a control group now.

Historical controls lessen the number of patients required to conduct a trial and simplify trial execution.

DATA MANAGEMENT

Several experts addressed methods of handling data, including ways of compensating for gaps in data or for missing data from patients who didn’t complete a trial.

The need for various levels of safety monitoring, depending on the expected risks of the trial, were discussed.

Safety monitoring boards are sometimes aware of which participants are getting which treatment (“unblinded” boards) and sometimes unaware (“blinded” boards).

Boards have the responsibility to recommend stopping a trial if they observe an unacceptable level of adverse events (harm to participants).

REGULATIONS

Bernard Ravina of the National Institute of Neurological Disorders and Stroke of the National Institutes of Health discussed the role of NIH in supporting and funding clinical trials, while Marc Walton of the U.S. Food and Drug Administration spoke about the FDA’s requirements for conducting clinical trials.

GETTING TOGETHER

The third day of the conference was devoted to a discussion of collaborative research groups. The main ALS research groups in the United States are the Western ALS (WALS) Group, the New England ALS (NEALS) Group, and the Great Lakes ALS (GLALS) Group.

The audience also heard about the Canadian ALS group and the European ALS Consortium.

The purposes of these groups are to accumulate enough participants to achieve a statistically significant result in a clinical trial; share data and sometimes DNA or tissue samples, as well as ideas; and present convincing trial designs to funding agencies.

Much of the discussion of the third day centered around when and whether all U.S. or perhaps all North American ALS groups should create one large organization that would theoretically be able to realize all those purposes most efficiently.

The downside of such an endeavor was also mentioned, with some audience members and speakers expressing concern about the loss of autonomy of the regional groups within the North American group and perhaps less tolerance of junior members or innovative ideas should the new organization become too large and bureaucratic.

The group voted to set up a nominating committee that will in turn propose a steering committee to develop a national or North American ALS research group.

TAKING ACTION

Lewis P. Rowland, founder and former director of the MDA/ALS Center at Columbia Presbyterian Medical Center and now a professor of neurology at that institution, closed the conference by voicing several calls to action for the conferees.

These were to

• plan regular meetings with the aim of improving trial designs
• organize a national consortium, one of the goals of which should be to train clinical investigators
• improve clinical trials, making sure the trials have adequate power to show the effects they seek to show
• continue with stem cell and gene therapy research in ALS, as well as with conventional drug research
• reconsider drug screening that uses rodent models, since it has not been able to predict human responses in most cases, and to consider whether molecular screening techniques might be better
• develop a new generation of ALS investigators by seeking solutions to the problem of financial obstacles that may deter professionals from entering this field.